1. Field of the Invention
The invention is concerned with an improved process for the large scale production of N-[3-(1H-imidazol-1-yl)phenyl]-4-(substituted)-2-pyrimidinamines, wherein the substituent is selected from the group consisting of 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-furanyl and 2-thienyl.
2. Description of the Prior Art
As disclosed in U.S. Pat. No. 4,788,195, the N-[3-(1H-imidazol-1-yl)phenyl]-4-(substituted)-2-pyrimidinamine compounds are known anti-asthma agents. This patent also discloses a method for producing such compounds from [3-(1H-imidazol-1-yl)phenyl]guanidine and an appropriate enaminone.
The '195 patent describes making the guanidine by adding 3-(1H-imidazol-1-yl)benzamine to a solution of HCL, in ethanol, adding cyanamide and warming. This method of making a guanidine from the reaction of the mineral acid salt of an amine with cyanamide is well known (See J. Medicinal Chemistry, 1975, vol 18 no. 11 p 1077-10883 and Synthesis, September 1986, p 777-779). These references do not disclose or suggest controlling pH within any particular range during the amine, HCL and cyanamide reaction to form the guanidine.
The '195 patent describes forming the desired N-[3-(1H-imidazol-1-yl)phenyl]-4-(substituted)-2-pyrimidinamines by reacting the crude guanidine without further purification with an appropriate enaminone in the presence of a base. The desired products are recovered by precipitation and recrystallization steps. Example 328 of U.S. Pat. No. 4,788,195 describes the formation of N-[3-(1H-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2pyrimidinaine at a yield of 26%. Other relevant Examples include 220, 231, 232 and 233. While these described procedures and yields are quite acceptable on an experimental scale, a greater yield would be more desirable for a large scale or commercial process.